title: Role of YKL-40 in the angiogenesis, radioresistance, and progression of glioblastoma.
abstract: Glioblastoma is one of the most fatal cancers, characterized by a strong vascularized phenotype. YKL-40, a secreted glycoprotein, is overexpressed in patients with glioblastomas and has potential as a novel tumor biomarker. The molecular mechanisms of YKL-40 in glioblastoma development, however, are poorly understood. Here, we aimed to elucidate the role YKL-40 plays in the regulation of VEGF expression, tumor angiogenesis, and radioresistance. YKL-40 up-regulated VEGF expression in glioblastoma cell line U87, and both YKL-40 and VEGF synergistically promote endothelial cell angiogenesis. Interestingly, long term inhibition of VEGF up-regulated YKL-40. YKL-40 induced coordination of membrane receptor syndecan-1 and integrin αvβ5, and triggered a signaling cascade through FAK(397) to ERK-1 and ERK-2, leading to elevated VEGF and enhanced angiogenesis. In addition, γ-irradiation of U87 cells increased YKL-40 expression that protects cell death through AKT activation and also enhances endothelial cell angiogenesis. Blockade of YKL-40 activity or expression decreased tumor growth, angiogenesis, and metastasis in xenografted animals. Immunohistochemical analysis of human glioblastomas revealed a correlation between YKL-40, VEGF, and patient survival. These findings have shed light on the mechanisms by which YKL-40 promotes tumor angiogenesis and malignancy, and thus provide a therapeutic target for tumor treatment.
authors.affiliation: Molecular and Cellular Biology Program, Morrill Science Center, University of Massachusetts, Amherst, Massachusetts 01003, USA.
authors.forename: Ralph A
authors.initials: RA
authors.lastname: Francescone
authors.forename: Steve
authors.initials: S
authors.lastname: Scully
authors.forename: Michael
authors.initials: M
authors.lastname: Faibish
authors.forename: Sherry L
authors.initials: SL
authors.lastname: Taylor
authors.forename: Dennis
authors.initials: D
authors.lastname: Oh
authors.forename: Luis
authors.initials: L
authors.lastname: Moral
authors.forename: Wei
authors.initials: W
authors.lastname: Yan
authors.forename: Brooke
authors.initials: B
authors.lastname: Bentley
authors.forename: Rong
authors.initials: R
authors.lastname: Shao
mesh_terms: D054392:Adipokines; D000818:Animals; D045744:Cell Line, Tumor; D000071451:Chitinase-3-Like Protein 1; D018450:Disease Progression; D005720:Gamma Rays; D005909:Glioblastoma / Q000098:blood supply / Q000473:pathology* / Q000532:radiotherapy; D006023:Glycoproteins / Q000032:analysis / Q000037:antagonists & inhibitors / Q000502:physiology*; D006801:Humans; D037102:Lectins / Q000032:analysis / Q000037:antagonists & inhibitors / Q000502:physiology*; D009362:Neoplasm Metastasis; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000209:etiology*; D015996:Survival Rate; D014183:Transplantation, Heterologous; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis / Q000235:genetics*
chemical_list: D054392:Adipokines; C084533:CHI3L1 protein, human; D000071451:Chitinase-3-Like Protein 1; D006023:Glycoproteins; D037102:Lectins; D042461:Vascular Endothelial Growth Factor A